Extended release tablets that have an osmotically active drug core surrounded by a semipermeable membrane are known in the art. These osmotic dosage forms function by allowing water, from gastric or intestinal fluid, to flow through the semipermeable membrane and dissolve the active ingredient in the core so it can be released through one or more passageways created in the membrane. An elementary osmotic delivery system requires that the drug be in solution in order to be delivered in a controlled and predictable manner. The drug in solution is pumped out due to the osmotic gradient generated across the semipermeable membrane.
If the drug is insoluble, an elementary osmotic system will not function properly. One approach for delivering pharmaceutical agents that are insoluble in aqueous solvents was developed by Kuczynski et al., (U.S. Pat. No. 5,545,413). In their approach, the interior of the tablet or capsule is characterized by two core layers, one containing the pharmaceutical agent (again to be released through openings, or holes, in the wall of the tablet or capsule) and the other being a layer of material that swells when coming into contact with water. The material that swells or expands to an equilibrium state when exposed to water or other biological fluids is referred to as an “osmopolymer”. This volume expansion is used to physically force the pharmaceutical agent out through openings, which have been formed in the wall, shell or coating during manufacture. The pharmaceutical agent is primarily released as insoluble particles, which therefore have limited bioavailability. This has commonly been referred to as the “push/pull” approach. See, for example, U.S. Pat. Nos. 5,422,123; 4,783,337; 4,765,989; 4,612,008; and 4,327,725. The patent literature has taught that this approach was necessary to deliver adequate doses, at controlled rates and for extended times, of a broad variety of drugs.
Other osmotic delivery systems have also been described. See, for example, U.S. Pat. Nos. 4,609,374; 4,036,228; 4,992,278; 4,160,020; and 4,615,698. The osmopolymers used in these types of systems are components whose functions are to swell when they interact with water and aqueous fluids. This swelling effect is defined in these patents as a property of imbibing fluid so as to expand to a very high degree, usually exhibiting a 2 to 50-fold volume increase.
Rudnic et al., (U.S. Pat. Nos. 6,110,498; 6,284,276; 6,361,796, and 6,514,532) used sodium lauryl sulfate and other solubilizers to enhance the solubility of glipizide, a poorly soluble drug, to deliver it from an elementary type of osmotic system in a sustained manner. This system of Rudnic is comprised of (a) a semi-permeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passage there through; (b) a single, homogeneous composition within said wall, which composition consists essentially of (i) a pharmaceutically active agent, (ii) at least one non-swelling solubilizing agent which enhances the solubility of the pharmaceutically active agent; (iii) at least one non-swelling osmotic agent, and, optionally, (iv) a non-swelling wicking agent dispersed throughout the composition which enhances the surface area contact of the pharmaceutical agent with the incoming aqueous fluid.
A limitation of the system of Rudnic is that none of the solubilizers disclosed are capable of fully solubilizing glipizide, an example of a hydrophobic active agent, in the core after the osmotic pill is ingested. Although this system provided improvements to the state of the art, this limitation may lead to erratic and unpredictable release profiles.
Glipizide is one of many poorly water-soluble drugs. According to the 2002 edition of the USP (USP25, NF20), glipizide is considered practically insoluble in water (solubility is in the range of 23 μg/ml). The solubility of glipizide is a limiting factor in its ability to be delivered from an osmotic drug delivery system.
Thombre et al., (U.S. Pat. No. 5,697,922) used meglumine as a solubilizing agent for glipizide. They coated meglumine with semi-permeable polymeric films to extend the release of the solubilizer from the core. They argued that non-encapsulated solubilizers would leave the core early, leaving the drug behind in unsolubilized form. This loss of solubilizer results in erratic release or no release at all. The problem with this approach is that it is very complex, because it involves coating of the solubilizing excipient in the manufacture of the tablet. This process limits its practical significance. Also, the amount of solubilizing excipient used in this approach is exceedingly high. See also, U.S. Pat. No. 5,698,220, which discloses the use of 90% meglumine (aka, N-methylglucamine) in an osmotic dosage form for delivering glipizide.
The present invention overcomes the inadequacies of the prior art by providing ways to increase the solubility of glipizide and other poorly soluble drugs so that they can be delivered to a mammal in a safe and more effective manner. Moreover, the present invention will assist in the delivery of other compounds that have higher aqueous solubilities, but which suffer from erratic delivery from an osmotic system because of high drug load, a problem that has not been addressed in the prior art. The invention is exemplified by a drug with particularly poor water solubility, glipizide, which has presented problems with the prior art technology, and which substantiates the broad utility of the present invention.